An international team of researchers supported by the National
Institutes of Health (NIH) has blocked staph infections in mice
using a drug previously tested in clinical trials as a cholesterol-lowering
agent. The novel approach, described in the February 14 online
edition of Science, could offer a new direction for therapies
against a bacterium that's becoming increasingly resistant
to antibiotics.

"By following their scientific instinct about a basic biological
process, the researchers made a surprising discovery with important
clinical implications," said NIH Director Elias A. Zerhouni,
M.D. "Although the results are still very preliminary, they
offer a promising new lead for developing drugs to treat a very
timely and medically important health concern."

This work was supported by three NIH components: the National
Institute of General Medical Sciences, the National Institute of
Allergy and Infectious Diseases, and the National Institute of
Child Health and Human Development.

A pigment similar to the one that gives carrots their color turns Staphylococcus
aureus ("staph") golden. In the bacterium, this
pigment acts as an antioxidant to block the reactive oxygen molecules
the immune system uses to kill bacteria.

Researchers had speculated that blocking pigment formation in
staph could restore the immune system's ability to thwart
infection. While perusing a magazine on microbial research, Eric
Oldfield, Ph.D., of the University of Illinois at Urbana-Champaign
read how in 2005 University of California, San Diego researchers
knocked out a gene in staph's pigment-making pathway to create
colorless — and less pathogenic — bacteria.

"I looked at the metabolic pathway and noticed that it was
similar to the one for the production of cholesterol in humans," said
Oldfield, senior author of the Science paper, who had
spent decades studying this pathway. With numerous cholesterol-lowering
drugs already on the market and in development, he wondered if
any could turn staph colorless and make them once again susceptible
to the immune system.

Colleagues in Taiwan determined the structure of the enzyme that
triggers the first critical step in staph's pigment formation
and observed striking similarities to an enzyme involved in human
cholesterol production. They also captured the structures of several
cholesterol-lowering drugs bound to the bacterial enzyme.

Building on their 2005 research that sparked the current study,
Victor Nizet, M.D., and George Liu, M.D., Ph.D., now at Cedars-Sinai
Medical Center in Los Angeles, Calif., tested eight different drug
compounds that act on the human cholesterol enzyme. Three blocked
pigment production in laboratory tests. When the researchers treated
mice infected with S. aureus with one of the compounds,
the bacterial population was reduced by 98 percent.

Because the approach reduces the virulence of the bacteria by
stopping pigment production, it may not cause selective pressures
on the population, which can lead to antibiotic resistance. It
also targets only S. aureus, possibly reducing side effects.

"This is an entirely new approach that seems to work in
animals, and now we need to take the next step to explore if it
will work in humans," said Oldfield.

Contributing authors also include Chia-I Liu, Ph.D., Wen-Yih Jeng,
Ph.D., and Andrew H.-J. Wang, Ph.D., of the Academia Sinica in
Taipei, Taiwan; Mary E. Hensler, Ph.D., of the University of California,
San Diego; and Yongcheng Song, Ph.D., and Fenglin Yin, Ph.D., of
the University of Illinois at Urbana-Champaign.

NIGMS (http://www.nigms.nih.gov)
supports basic biomedical research that is the foundation for advances
in disease diagnosis, treatment, and prevention.

NIAID (http://www.niaid.nih.gov)
supports basic and applied research to prevent, diagnose, and treat
infectious diseases and also supports research on basic immunology,
transplantation, and immune-related disorders.

NICHD (http://www.nichd.nih.gov)
sponsors research on development, before and after birth; maternal,
child, and family health; reproductive biology and population issues;
and medical rehabilitation.

The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.